Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats
Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats
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DOI：
10.1097/00006123-199812000-00096
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发表时间：
1998-12-01
期刊：
影响因子：
4.8
通讯作者：
Dietrich, WD
中科院分区：
文献类型：
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作者：
Wada, K;Chatzipanteli, K;Dietrich, WD
目的：研究外伤性脑损伤（TBI）后诱导型一氧化氮合酶（iNOS）酶活性的时间变化和iNOS表达的免疫细胞化学定位，以及iNOS在TBI发病机制中的可能作用。方法：雄性Sprague-Dawley大鼠麻醉后，进行中度矢状旁液击脑损伤。处死大鼠5分钟、6小时、1天、3天、7天、14天后，测定iNOS酶活性（n = 6 ~ 8）。为了确定iNOS产生的一氧化氮是否导致了TBI的组织病理学后果，使用氨基胍（每天两次，腹腔注射100 mg/kg氨基胍[n = 9]或对照物[n = 8]）抑制iNOS活性，持续3天。结果：脑损伤后第3天iNOS活性显著升高（对侧值的276.8 +/- 72.3%，平均+/-标准误差，P < 0.05），损伤后第7天脑顶叶皮层iNOS活性升高最为明显（608.0 +/- 127.0%,P < 0.01）。脑外伤后第3天和第7天iNOS和胶质原纤维酸性蛋白的免疫染色显示，iNOS表达的主要细胞来源是皮层第1层星形胶质细胞和蛛网膜下腔内的巨噬细胞。给药氨基胍没有显著降低挫伤体积；然而，治疗减少了皮质坏死神经元总数（1367.6 +/- 210.3;P < 0.01，与对照组相比，2808.5 +/- 325.1）。结论：这些数据表明，中度旁矢状面液体冲击脑损伤后iNOS表达呈时间依赖性，抑制iNOS合成可改善组织病理学结果。因此，抑制iNOS激活可能是治疗TBI的一种潜在的治疗策略。
OBJECTIVE: We investigated the time course of inducible nitric oxide synthase (iNOS) enzymatic activity and immunocytochemical localization of iNOS expression after traumatic brain injury (TBI), as well as the possible role of iNOS in the pathogenesis of TBI.METHODS: Male Sprague-Dawley rats were anesthetized and underwent moderate parasagittal fluid-percussion brain injury. Rats were decapitated 5 minutes, 6 hours, 1 day, 3 days, 7 days, or 14 days later, and iNOS enzymatic activities were measured (n = 6-8). To determine whether nitric oxide produced by iNOS contributed to the histopathological consequences of TBI, inhibition of iNOS activity using aminoguanidine (intraperitoneal injections of 100 mg/kg aminoguanidine [n = 9] or vehicle [n = 8], twice each day) was conducted for 3 days.RESULTS: Significantly elevated iNOS activity was detected at 3 days (276.8 +/- 72.3% of contralateral value, means +/- standard errors; P < 0.05), and the most robust increase occurred 7 days after TBI (608.0 +/- 127.0%, P < 0.01) in the injured parietal cerebral cortex. Immunostaining for iNOS and glial fibrillary acidic protein, at 3 and 7 days after TBI, revealed that the major cellular sources of iNOS expression were cortical Layer 1 astrocytes and macrophages within the subarachnoid space. Administration of aminoguanidine did not reduce contusion volume significantly; however, treatment reduced total cortical necrotic neuron counts (1367.6 +/- 210.3; P < 0.01, compared with vehicle, 2808.5 +/- 325.1).CONCLUSION: These data indicate that iNOS is expressed after moderate parasagittal fluid-percussion brain injury, in a time-dependent manner, and that inhibition of iNOS synthesis improves histopathological outcomes. Thus, inhibition of iNOS activation may represent a potential therapeutic strategy for the treatment of TBI.